1. Description of the problem

What every clinician needs to know

A condition related to increased cell turnover and cell death. As cells die, they release intracellular contents such as phosphorous, potassium, and DNA which is degraded to uric acid.

All complications of tumor lysis syndrome relate to hypocalcemia, hyperphosphatemia, hyperkalemia, and renal insufficiency due to tubular deposition of uric acid and calcium phosphorous crystals.

Hyperkalemia is generally only a problem in pediatric patients once renal insufficiency becomes severe.

Cancers most frequently associated with TLS include any leukemia or lymphoma with high tumor burden (hyperleukocytosis, bulky disease), especially Burkitt's lymphoma which has the most rapid doubling time of any pediatric cancer.

TLS may begin before initiation of chemotherapy, or after the first dose. Rarely solid tumors such as neuroblastoma or hepatoblastoma have TLS as a complication of the first chemotherapy treatment. Some non-malignant conditions such as rhabdomyolysis may also be associated since they also have massive cell death.

Three factors contribute to TLS:

Does laboratory evidence of TLS exist at presentation?

What is the type of cancer and LDH?

Is there underlying renal dysfunction, either chronic or acute?

Hyperleukocytosis

Defined as a peripheral white blood cell count greater than 100,000 cell/microl. This is seen almost exclusively in acute leukemia, both myeloid and lymphocytic. Chronic myelogenous leukemia (CML) is rarely seen in the pediatric population, but commonly presents with a WBC greater than 100,000.

For acute lymphocytic leukemia (ALL), a WBC greater than 100,000 cell/microl places the patient in a higher risk group, increasing the amount of chemotherapy that they need.

Acutely elevated white count signifies a greater risk of TLS. Ischemic stroke or hemorrhage are rare complications of hyperleukocytosis in ALL, and do not generally present until the WBC is greater than 300,000 cells/microl. Chemotherapy is usually sufficient to treat patients with WBC less than 300,000 cells/microl.

For acute myeloid leukemia (AML), a WBC of greater than 200,000 implies a higher risk of pulmonary leukostasis and cerebral events (both ischemic and hemorrhagic). TLS is less common in AML as the cells are not as susceptible to chemotherapy. Leukopheresis is needed more commonly in AML with hyperleukocytosis.

For patients with CML, there is little pediatric data discussing the risk of hyperleukocytosis. Older publications feel there is a greater risk of cerebral events related to CML in children when compared to adults, but this is not proven. Therefore the decision for leukopheresis is an individual decision.

MM

Associated with bulky disease in the chest. Most commonly this is due to a T-lineage leukemia or lymphoma with thymic infiltration. This can also result from primary solid tumors which occur in the chest, such as sarcoma, neuroblastoma, or germ cell tumor. Lastly, this can result from mediastinal or pulmonary lymph nodes with metastatic disease.

These masses potentially can compress the trachea or mainstem bronchi obstructing airflow. Usually the obstruction is relatively low in the airway, so that emergent airway interventions (such as intubation or tracheotomy) cannot relieve the obstruction. This should be considered a medical emergency whenever it is suspected, even with minimal symptoms.

SVCS

Results when blood return from the upper body to the heart is obstructed. Generally this occurs at the level of the superior vena cava (SVC), and is due to external compression by a tumor mass or occlusive thrombosis within the SVC, or both. Rarely this is a complication of tuberculosis.

FN

Neutropenia is defined differently depending on the source, but is usually always defined as an absolute neutrophil count (ANC) which is less than 1000 neutrophils/ml. ANC is calculated by taking the total WBC and multiplying that number by the percentage of segs +bands (WBC x (%seg + %band)).

Mild risk occurs with an ANC less than 750 cells/microl, moderate risk occurs with an ANC less than 500 cells/microl, and high risk occurs with an ANC less than 200 cells/microl.

Patients with low ANC and fever are at risk for bacteria translocating across the mucosal barrier of the intestine. Therefore, pseudomonas and other gram negative enteric bacteria are of primary concern. Other sources of bacteria include the skin and oral cavity, so gram positive infection and anaerobic infections also need to be considered.

When there is true neutropenia (low ANC, and a marrow which is unable to mount a stress response - ex a child after chemotherapy) signs and symptoms of infection may be absent. Traditional signs of inflammation (heat, redness, pain, swelling) are mediated by the white cells, and not by the bacteria. Therefore a patient with a low ANC may have a severe infection without significant clinical findings.

Typhlitis

Typhlitis is bacterial overgrowth in the small and large intestine, usually in the setting of neutropenia. In many ways this is a similar process to necrotizing enterocolitis (NEC) in the neonatal population. For patients in induction for leukemia, up to 30% of patients may show signs of typhlitis. Classic typhlitis localizes to the right lower quadrant, but typhlitis is now known to occur throughout the intestine, and should be considered in any patient with acute abdominal pain and neutropenia with or without fever.

Typhlitis increases the risk of fever associated with neutropenia, bacteremia, and sepsis. It is also associated with complication of the bowel including constipation, pneumatosis, perforation, and GI bleed. Early recognition and appropriate treatment minimizes these complications.

SCC

A serious oncological complication which may or may not be life threatening depending on the spinal level involved; nevertheless this should be considered a medical emergency regardless, given the long term effects on mobility and function.

SCC can be caused by several oncological processes. Bone metastasis to vertebral bodies can extend to the epidural space compressing the spine; tumors may directly intrude through the neural foramen; brain tumors may have drop metastasis within the CSF space; chloromas (collections of malignant white blood cells, typically seen in acute leukemias) may form anywhere in the body, including the spine; associated conditions such as sepsis and DIC can lead to bleeding and hematoma formation.

Treatment needs to be initiated quickly to preserve function, and should be modified according to the cause of compression. Five percent of all oncology patients will have evidence of spinal cord compression.

Clinical features

TLS

Laboratory evidence of TLS include an elevation of two of the three following: phosphorous, potassium or uric acid levels.

Elevation of LDH >2x's normal is a risk factor for some tumors with a predisposition for TLS.

Historical findings for MM include difficulty breathing. Initially symptoms may present with increased activity or air movement, such as with exercise, and progress to positional changes (more difficulty while lying flat). Upper airway obstruction (outside the thoracic cage) generally presents with stridorous sounds, and any history of this in a child with suspected malignancy should be evaluated. Wheezing is indicative of an obstructing intrathoracic mass.

SVCS

Swelling or discoloration of one or both upper extremities is the hallmark of diagnosis. Having a CVL in the venous system increases the risk of thrombosis if this occurs after initial diagnosis. History of a previous central line may also predispose to venous thrombosis. Swelling may also involve the head and neck in severe cases.

Respiratory distress can be a component of the syndrome due to mass effect on the trachea or mainstem bronchi. This can be manifested subjectively by increased anxiety or a feeling of air hunger. Clinically, stridor would indicate extrathoracic compression of the airway; there may be deviation of the trachea.

Changes in mental status are late findings, and may reflect increased intracranial pressure due to obstruction of venous outflow from the CNS. Venous infarction of the CNS is possible and can present with focal neurologic findings.

FN

Clinically, the only finding may be fever. Associated findings related to a period of pancytopenia include decreased energy due to anemia, and possible skin or mucosal bleeding due to thrombocytopenia. GI associated findings can include mucositis and abdominal pain. Other symptoms would be chemotherapy specific.

During a period of neutropenia (ANC < 500), there may be no associated physical findings (redness, swelling, warmth) present to localize the infection. Any area associated with pain should be fully evaluated in a child with FN. Special attention should be provided to mucosal surfaces, the abdomen, the genitalia and perirectal area, and skin looking for apparently small and seeming innocuous sites of infection. These areas may indicate sites of severe infection.

Under no circumstances should any instrument be placed in the rectum, due to the risk of causing bacteremia. Central line, if present, must be evaluated for possible infection.

Typhlitis

Clinical findings are related to abdominal pain, usually during an episode of neutropenia, with or without fever. Most frequently, this pain is of intermediate severity and generalized, but can be severe enough to require narcotics, even PCA narcotic infusions. Increasing severity especially associated with focal areas of pain, should raise concerns for a surgical abdomen.

Conditions such as bacteremia, sepsis, and DIC may be more frequent when neutropenia is associated with typhlitis. Constipation and diarrhea may both occur. Constipation if preceding the typhlitis, may contribute.

SCC

A detailed history of the patient with newly diagnosed malignancy should always be obtained. The history that emphasizes possible SCC would be increasing weakness and inability to walk. A recent history of incontinence, especially for stool, in a toilet trained child should always raise the suspicion of SCC. Numbness over a similar distribution is important to determine.

Eighty percent of patients with spinal cord compression due to vertebral metastasis have back pain by history.

Physical exam may demonstrate point tenderness over the vertebral bodies. Neurologic exam depends on the level of compression. Neurologic symptoms will include motor weakness below the level of compression, with upper motor neuron findings including hyperreflexia. Reflexes may be absent at the exact level of compression due to interruption of the reflex arc. Bowel and bladder function may be compromised, and there may decreased rectal tone.

Detailed sensory exam may show a sensory level, which is one of the easiest ways to determine the level of SCC. If the compression occurs at the level of the cervical spine, upper extremities may be involved. Involvement on C5 and above may impair the function of the phrenic nerve and movement of the diaphragm.

Maximize urine output with fluids while completing risk assessment if the patient has adequate urine output.

Treatment for specific abnormalities:

Treatment of elevated uric acid according to risk group (low, intermediate, high).

Treatment of elevated phosphorous and decreased calcium.

Emergent treatment of hyperkalemia if it exists.

Treatment of renal failure with dialysis if indicated.

Consult hematology oncology for appropriate chemotherapy.

Hyperleukocytosis

Goals are to prevent TLS, CNS events, and ARDS.

Assessment of Tumor lysis syndrome as above.

Assessment of mediastinal mass with CXR.

Close monitoring of neurologic and pulmonary status.

Arrange for leukoreduction via plasmapheresis or double volume exchange depending on patient weight and available resources (does the hospital have a pheresis service?).

Consult hematology/oncology service for appropriate chemotherapy.

MM

Goal is to prevent upper airway obstruction which is most likely below the level of intubation.

Ensure that the patient is fully awake and in a position of maximal comfort. At the most extreme, this will be the tripod position with the patient sitting up and leaning their chest forward.

Avoid any sedation which may reduce respiratory effort, or eliminate the use of secondary muscles of respiration. These forces may be the only force keeping the tumor from collapsing the airway. Any diagnostic procedure should be done under local anesthesia.

Consult hematology/oncology service for appropriate and emergent chemotherapy or radiation. Treatment should not be held for diagnostic procedures if the patient is clinically in danger of losing their airway.

SVCS

Goal is to prevent venous infarction of the brain, or acute pulmonary embolism.

If SVCS is suspected, determine if the etiology is thrombosis within the vessel, or external compression. This can be accomplished readily with CT scan if the patient is stable.

If obstruction is due to compression, follow the MM goals above.

If obstruction is due to venous thrombosis, begin heparin drip or low molecular weight heparin (LMWH) per institutional protocols. More invasive therapies, such as thrombolytics, are judged on a case by case basis.

FN

Goal is to prevent overwhelming sepsis.

Once a patient, who may be neutropenic, presents to a facility, the patient should be immediately assessed, CBC and blood cultures drawn from the central venous line (CVL), and initial dose of and antipseudomonal IV antibiotic should be given. At our institution, the antibiotic is given prior to determining if the patient is neutropenic to prevent treatment delays.

Even minimal signs and symptoms of sepsis should be treated aggressively with fluid boluses and early use of dopamine to support the blood pressure if necessary. Labs to assess DIC should be obtained if the patient is even minimally sick. Full physical exam to assess for sites of infection should be done early in the assessment, as this may change the antibiotic choice.

Establish the risk of the patient with fever and neutropenia and expand coverage appropriately. Examples of our institution's risk categories follows:

Low risk (treatment with a single antipseudomonal cephalosporin, synthetic penicillin, or carbapenem is adequate):

Primary diagnosis of a solid tumor, or a leukemia or lymphoma IN REMISSION. Note that AML is NEVER considered low risk at any time during treatment.

Duration of current neutropenia at time of presentation is less than 7 days; expected duration of neutropenia is less than 10 days.

No localizing signs or symptoms described below.

No mucositis.

No recent history of line infection which may be recurring.

High risk (requires the treatment for low risk, plus gram positive treatment. In our institution initial therapy is with vancomycin):

Leukemia or lymphoma that is not in remission; AML at any time on therapy

Evidence of line infection (chills with line flush, recent line infection just off therapy)

Any type of cellulitis. Many times this may be in association with a G-tube, or entry site for any catheter.

Mucositis or history of chemotherapy that is associated with mucositis such as high dose cytarabine (standard AML therapy)

Abdominal source (should treat with high risk therapy, and expand coverage to include anaerobes. In our institution, this is done by changing the 3rd generation antipseudomonal cephalosporin to a carbapenem, meropenem, which covers both gram negative infections including pseudomonas, as well as anaerobes.

Any abdominal pain on exam.

Evidence of abscess on exam. Close attention should be paid to the perirectal exam, which should be done on every neutropenic patient. Any erythema, tenderness or swelling should be considered an abscess, even if there is no clear exam or radiologic findings.

Unstable with evidence of shock before or after initial antibiotic dose (broadest coverage with double coverage for pseudomonas, gram positive coverage, and anaerobic coverage. In our institution this is done with a combination of meropenem, vancomycin and an aminoglycoside).

Typhlitis

Goal is to prevent overwhelming sepsis and to control related abdominal symptoms such as constipation and pain.

Initiate the appropriate antibiotics as per the fever neutropenia guidelines above.

Assessment of a possible surgical abdomen; if rebound or guarding is present, then further assessment with imaging such as KUB or abdominal US may be needed. Pediatric surgery consult should be considered.

Initiate pain control as needed. This may require narcotics and patient-controlled analgesia devices.

Management of constipation or diarrhea as warranted. Severe constipation can be worsened with narcotics, and can increase the risk of complications associated with typhlitis.

Management of nutritional support.

SCC

Goal is to prevent long term loss of function (para- or quadriplegia) or, if the site of compression is high enough, loss of diaphragm function with respiratory failure.

Immediate discussion with neurosurgery and hematology/oncology.

Neurosurgery may wish to initiate steroids at doses for spinal cord injury. Be aware that these may cause other complications such as TLS. This is not a contraindication to the use of steroids, but should be considered.

Emergent imaging of the spine usually with MRI to localize level of compression.

Immediate treatment, which may include surgery, chemotherapy, or radiation. Chemotherapy has been shown to work as well as laminectomy in retrospective series at least in neuroblastoma. The decision of how to treat should be reached with a consensus of the treating services.

2. Emergency Management

Stabilizing the patient

TLS

Initial assessment:

Assess volume status to ensure there are no life threatening conditions (pulmonary edema in the setting of renal failure).

Document last urine output by history or medical record to ensure that the patient still has urine output before initiating hydration.

Begin hydration at 1.5 x maintenance using D5-1/2NS WITHOUT potassium. Based on the child's clinical appearance hydration may be increased to 3x maintenance or more, but the patient should be closely monitored in those cases for signs of iatrogenic fluid overload. Bicarbonate may be added to the fluids to alkalinize the urine if urate oxidase will not be used. Urine output goal is 2-3 cc/kg/hour.

Assessment of electrolytes:

Frequent and repeated assessment of electrolytes.

Calcium (hypocalcemia):

If normal, no action needed.

If low, but asymptomatic (no heart failure of seizure activity) or muscle spasm is present, observe or initiate oral calcium.

If symptomatic hypocalcemia results (seizures, heart failure), IV calcium may be initiated with the caveat that precipitation of calcium phosphorous crystals may occur in the soft tissues. If it occurs in the renal tubules it may worsen renal failure.

Phosphorous (hyperphosphatemia):

Initial Amphojel to absorb dietary sources of phosphorous.

Low phosphorous diet (this should be B.4) uric acid (hyperuricemia).

Hyperkalemia (See Table I)

If potassium levels are higher than 6 mEq/dl, obtain EKG. If there are EKG changes that are attributable to hyperkalemia (peaked T waves, loss of P wave, widened QRS complex, sign wave), or if there are clinical findings of shock secondary to arrhythmia or EMD, treat immediately.

If acute treatment is initiated for hyperkalemia, Kayexalate should be given immediately, and dialysis considered.

High risk of TLS: (high risk tumors, or low risk or intermediate risk tumors with laboratory evidence of TLS or renal dysfunction at presentation):

Treat with IV hydration and rasburicase.

D. Renal failure

Hydration as described above

Close monitoring of urine output and BUN/creatinine

Close monitoring of electrolytes

Early consideration of nephrology consult and dialysis

Hyperleukocytosis

Evaluate for TLS as above

Assess for MM as below

Assess respiratory status and CNS status

Initiate IVF at 1.5 maintenance

Hyperleukocytosis requires rapid reduction for the following cases.

Lymphoid malignancy: WBC > 300,000

Myeloid malignancy: WBC >200,000

Chronic myelogenous leukemia (CML): WBC> 300,000

If deemed a medical emergency, at risk for significant side effects, consider initial therapy as follows:

<10 kg and - symptomatic, or at high risk of complications:

Begin chemotherapy in consultation with pediatric oncology

Consider CVL placement for steps c and d below

Consultation with the local red cross or pheresis service to see if the patient is a candidate for leukopheresis

If not, consider double exchange transfusion:

Estimated volume of total exchange is 160 cc/kg.

The hematocrit of PRBC (usually 60-70%) must be dropped to appropriate levels using NS or albumin.

In general the hematocrit of the exchanged blood should not be higher than 30. If the patients hematocrit is <15, do not raise the hematocrit by more than 10% over the original Hct (ex: if the original Hct is 12%, final Hct after exchange transfusion should not be more than 22%). If the hematocrite is raised above 30%, the risk of vascular occlusion due to increased viscosity will increase, especially in AML.

Two lines must be established, one to pull blood from, and one to put blood into. A double lumen CVL will work if blood is taken from the proximal opening and placed into the distal opening.

Small amounts of the patient's blood 3-5 cc (depending on the patient's size) should be pulled from one line. Then small aliquots of PRBC (the same volume as taken), reconstituted to the appropriate hemoglobin should be infused in the other line. Aliquats should be placed and withdrawn every 3-5 minutes until 160 cc/kg is infused.

Calcium supplements may be needed due to the anticoagulant (citrate) in the PRBC to help prevent coagulopathy.

Large volume exchange transfusion can exacerbate DIC. Be prepared to transfuse fresh frozen plasma if needed.

>10 kg and - symptomatic or at high risk for complications:

Begin chemotherapy in consultation with pediatric oncology

Consider CVL placement for steps c and d below

Consultation with the local red cross or pheresis service to see if the patient is a candidate for leukopheresis

If not available consider double volume exchange described above

Continue pheresis daily until total white count is under 100,000; Exchange transfusions cannot be done daily without high risk of DIC.

Continue chemotherapy until determined by pediatric oncology.

MM

Evaluate for TLS as above.

Maintain position of comfort for the patient and prevent the patient from becoming anxious or agitated.

Consult hematology oncology for emergent management.

Diagnostic procedures should be done without sedation, using local anesthesia if possible. If diagnosis can be made via blood sample, this is ideal (blasts for leukemia/lymphoma, VMA and HVA for neuroblastoma, serum alpha-fetoprotein and beta hCG for germ cell tumors).

If the mass is an anterior mediastinal mass, and the patient is judged to be too unstable for diagnostic procedures, steroids should be initiated immediately at a dose of 40 mg/m2/day. TLS should be expected after steroid treatment.

If the mass is a posterior mediastenal mass, there should not be airway compromise, although there can be spinal cord compression. If emergent treatment is needed, the use of a general sarcoma treatment regimen should be considered such as vincristine, actinomycin-D and cyclophosphamide, or vincristine, doxorubicin, or cyclophosphamide.

In our institution, the following criteria are used to assess if a patient is safe for general anesthesia:

CT scan (or other cross sectional imaging) with less than 50% tracheal narrowing due to compression.

Peak expiratory flow of >50% expected. If either of these measurements is out of range the patient is at high risk of losing their airway during sedation.

Assessment of the pulmonary artery may also prove important. There are many reports of sudden death in the OR due to possible pulmonary artery compression in patients with mediastinal masses. There are no clinical criteria to assess whether a patient is at risk.

For intravascular initiate anticoagulation with either a heparin drip or LMWH per institutional guidelines. Other therapies such as thrombolysis must be considered in each case according to severity of the patient and the institutional resources.

For external compression, assess for MM and TLS as above. Emergent chemotherapy may be needed if the patient is having changes in mental status or evidence of venous infarcts in the CNS.

FN

Rapid assessment with vital signs and physical exam to determine perfusion status. If patient is in compensated or decompensated shock, consider those algorithms listed elsewhere in the module.

Immediate access of CVL with blood cultures and diagnostic blood tests needed by the assessing team.

Unstable with signs and symptoms of shock: antipseudomonal antibiotic with an aminoglycoside for double gram negative coverage, anaerobic coverage and gram positive coverage

Evidence of shock, compensated or uncompensated, either before or after initial antibiotic dose

Typhlitis

Follow FN protocols as explained above. If typhlitis is suspected coverage should be started for gram positive organisms, anaerobes, and gram negative organisms including pseudomonas.

Assessment of possible surgical abdomen. If rebound or guarding is seen, abdominal imaging should be considered, and surgical consultation should be obtained.

Treatment of pain which may be severe enough to warrant narcotics and patient-controlled analgesia devices.

Management of constipation, which can be worsened with the use of narcotics. Constipation can make the side effects of typhlitis more likely.

If prolonged stay is anticipated, consider TPN for nutritional support.

SCC

Full neurologic exam with both sensory and motor to determine the level of compression; palpation of the back and spine to determine if there is point tenderness which might suggest the level of compression.

Rapid imaging of the spine, usually with MRI, although CT may be adequate.

Rapid consultation with hematology oncology and neurosurgery to decide best treatment options as a team

Neurosurgery may want to treat with steroids per spinal injury protocols. Note that assessment of TLS should be done prior to and after the steroid dose if the suspected malignancy is lymphoid. Diagnosis may be compromised by steroids.

Treatment should be initiated as soon as possible, especially if the loss of function was rapid and recent (hours to days). Treatment should be decided on a patient by patient basis. Acceptable options include emergent laminectomy, emergent chemotherapy, or emergent radiation therapy. Generally surgery or chemotherapy are the first line options. In certain malignancies, such as neuroblastoma, there is evidence that chemotherapy is as effective as surgery.

Management points not to be missed

TLS

a. Checklist:

Establish history of UOP

Begin IVF at 1.5 maintenance

Frequent assessment of electrolytes, LDH and renal function

Emergent treatment for elevated potassium

Risk assessment of TLS as described above with appropriate therapy initiated

Manage secondary effect of hypocalcemia and hyperphosphatemia

Consult hematology oncology for chemotherapy

Consult nephrology for renal failure or hyperkalemia

b. Do not forget:

Do not forget to assess UOP prior to initiating IV hydration

Do not put potassium into the IVF until you are sure the risk of TLS has passed

Frequent assessment of electrolytes

Early nephrology consultation for dialysis if in renal failure

Do not assume high potassiums are due to hemolysis

Hyperleukocytosis

a. Checklist:

Rapid assessment of TLS, MM, neurologic status and respiratory status

Begin IVF at 1.5 maintenance

Initiate an exchange transfusion if patient is symptomatic or WBC is high enough

Contact local pheresis service if available

Order appropriate volume of PRBC, and order it reconstituted to the appropriate hematocrit with either NS or albumin

Establish venous access

Consult hematology oncology for chemotherapy recommendations

Do not forget

Associated with TLS and MM

Getting the blood for an exchange transfusion may take several hours depending on the location. Activate the blood bank as soon as possible if an exchange transfusion is needed.

Knowing your local pheresis service ahead of time can save hours in an emergent situation.

Line access is a critical part of pheresis. Make sure that you check with your service for their line

MM

a. Checklist:

If suspected, rapid CXR to confirm mass

Maintain the patient in a position of comfort, avoiding agitation and anxiety

CT scan of chest and peak expiratory flow rate if general anesthesia is considered critical

b. Do not forget:

General anesthesia will remove the increased work of breathing and the accessory respiratory muscles. In addition patient will generally be lying on their back. If a mediastinal mass occludes the airway, generally it is below the level of intubation. This leaves ECMO as the only sure way to establish gas exchange. Avoid general anesthesia.

Pulmonary artery compression is being recognized more frequently as a cause of sudden death during general anesthesia. There are no standards to judge compression, and this must be evaluated on a case by case basis.

SVCS

a. Checklist:

Assess for MM and TLS.

Establish mechanism of SVCS, whether it is due to external compression or intraluminal obstruction, generally with cross sectional imaging.

Emergent therapy may be needed if venous infarction is occurring in the CNS. Therapy is determined by the mechanism of SVCS

Thrombosis: Initiate anticoagulation with heparin (either unfractionated drip or LMWH) or other anticoagulant agent deemed appropriate. Consider thrombolysis of the SVC on a case by case basis if there is evidence of CNS infarction.

External compression (mass): Consider emergent treatment with chemotherapy, radiation or surgery based on the suspected malignancy and the clinical situation

b. Do not forget:

In children this can generally be managed conservatively by treating the patients primary tumor with front line therapy.

FN

a. Checklist:

Rapid assessment and triage once the patient presents.

Immediate access of CVL if present, and pan culture as appropriate to clinical presentation.

Immediate treatment with a antipseudomonal IV antibiotic.

Further history and physical to assess risk group and need for additional coverage (anaerobic, gram positive, additional gram negative coverage).

Frequent assessment of patient for signs and symptoms of shock (inadequate tissue perfusion).

Patient must be watched closely for the first 24-36 hours after presentation to ensure that signs and symptoms of shock do not develop.

Although FN protocols treat the most common infection, i.e. bacterial infection, in neutropenic patients, remember that other organisms, such as viruses and fungus, may also cause fever in these patients.

Typhlitis

a. Checklist:

Follow appropriate FN guidelines

Assessment of a surgical abdomen with exam and imaging

Pain control

Management of constipation or diarrhea

Management of nutrition with prolonged stay

b. Do not forget:

Typhlitis increases risk of sepsis and associated conditions such as DIC

Pneumatosis, perforation and GI bleed may complicate severe typhlitis

SCC

a. Checklist:

Decision making should be a team approach with neurosurgery, oncology and radiation oncology. There are tumors where chemotherapy will work as well as surgery.

Do not delay in the imaging of these patients.

Neurologic assessment should include rectal tone.

b. Do not forget:

Five percent of patients with malignancy will have SCC.

If steroids are given, recognize that they may cause TLS and delay the diagnosis of lymphoid malignancies.

3. Diagnosis

Diagnostic criteria and tests

All of these disorders are considered in the setting of a new or relapsed malignant diagnosis. Many times the challenge is to make the primary diagnosis of malignancy. Once a diagnosis of malignancy is made, these complications of malignancy should routinely be assessed.

TLS

Diagnostic criteria

Risk assessment of the cancer (diagnosis)

Clinical judgment based on presentation

Evaluation of the peripheral smear

Peripheral blood flow cytometry

Assessment of LDH

The diagnosis of a malignancy, particularly lymphoid, is enough to initiate prophylactic treatment of potential TLS.

Serum electrolytes (potassium, calcium, and phosphorous are most important)

Uric acid

BUN

Creatinine

LDH

EKG if potassium is elevated

Imaging

Generally not indicated

Consider renal US if TLS is severe and not responding as expected. Other causes of renal failure my exist (ex obstructive uropathy) which may have other treatments

Frequent reassessment of labs above

Hyperleukocytosis

Diagnostic criteria

Routine CBC will demonstrate hyperleukocytosis. Should make sure that the cytometer is able to read WBC >100,000 - many office practices will not have a machine that can read that high. Also need to correct for nucleated RBC's, although that is not usually an issue for WBC>100,000

MM

Diagnostic criteria

Any clinical evidence of extra or intra thoracic obstruction in the setting of a new diagnosis

Any imaging modality which demonstrates a thoracic mass

Diagnosis

Physical exam finding of a neck mass with tracheal deviation, or tracheal deviation or stridor alone in the setting of a new diagnosis

CXR is generally adequate to diagnose that a mass is present

CT of chest with contrast will give more information about degree of tracheal compression and allow at least partial assessment of pulmonary artery compression. Patient must be able to lie flat for this test.

Peak expiratory force may be obtained to see if there is significant airway compromise

SVCS

Diagnostic criteria

Findings of upper body edema, or neurologic changes and imaging that demonstrates compression or occlusion of the superior vena cava

Diagnosis

Generally requires imaging of the superior vena cava and is feeding tributaries. This may be done with a contrasted CT, contrasted MRI, MRV, or venogram.

FN

Diagnostic criteria

Any patient with an absolute neutrophil count (ANC) of <750 with signs or symptoms of fever or shock.

Note that fever is not an absolute criteria for diagnosing a neutropenic patient with FN and initiating antibiotic treatment, and that certain treatments such as dexamethasone, may mask fever in a septic patient.

Diagnosis

CBC with differential demonstrating an ANC <750

Fever or clinical signs and symptoms demonstrating possible infection. When in doubt, treat

Typhlitis

Diagnostic Criteria

Abdominal pain in the setting of neutropenia

Diagnostic tests

This is a primarily a clinical diagnosis

KUB may demonstrate obstruction or pneumatosis

Contrasted CT may demonstrate thickened walls in small or large bowel, traditionally, but not restricted to the cecum

SCC

Diagnostic Criteria

Neurologic findings compatible with compression of the spinal cord is sufficient to make a diagnosis

Diagnostic test

MRI or CT of the spine

Confirmatory tests

TLS

Image of EKG changes with hyperkalemia

Hyperleukocytosis

Smear? Not very helpful

MM

X-ray

One CT

SVCS

One CT

FN

Smear?

Typhlitis

CT of thickened bowel walls

SCC

MRI of SCC

Side effects

As stated above, the complexity of these side effects is diagnosing the underlying malignancy. Once that is diagnosed, these side effects should be routinely assessed. Therefore these are relatively specific. There may be other confounding complications which are listed with the specific disease.

leukemoid reaction due to inflammation such as sepsis (rarely reaches 100,000). Does not require treatment itself, just for the underlying inflammatory condition.

Transient myeloproliferative disorder (TMD) which occurs within the first year of life in patients with trisomy 21. Rarely these progress directly to leukemia over time. The natural course is for the white count to rise over weeks to months, sometimes over 100,000, possible with associated hepatosplenomegaly and lymphadenopathy, and then to gradually fall back to normal levels on its own without therapy. The entire time course may take 6-8 months or less. The patients with TMD need to be followed very closely afterwards as their risk of developing future leukemia is 25%.

MM

Any mass occupying lesion of the upper chest which could displace the trachea, such as an organized upper lobe pleural effusion or parenchymal consolidation.

SVCS

Obstruction of SVC may produce CNS symptoms.

FN

Adrenal insufficiency may contribute to hypotension especially if prolonged steroids have recently been used and weaned

Typhlitis

Any disorder leading to acute abdomen including common disorders such as appendicitis

SCC

Disorders which affect the spinal cord without mass effect such as transverse myelitis can present with similar neurologic features, but without associated back pain.

4. Specific Treatment

TLS

Diagnosis of the malignancy and Initiation of chemotherapy

Assessment of MM and hyperleukocytosis

Prevention of renal failure

IV hydration at 1.5 - 2.5 maintenance

Treatment by risk group above

Close monitoring of electrolytes, uric acid and renal function

Early consideration of dialysis if renal failure is progressive

Electrolyte disturbances

Oral calcium for hypocalcemia. Use IV calcium only if there is a risk of immediate injury to the patient

Oral phosphate binders to prevent further absorption of phosphorous

Early initiation of dialysis if renal failure is progressive

For symptomatic hyperkalemia (EKG changes) therapy as listed in the table above

Hyperleukocytosis

Assessment of MM and TLS

Diagnosis of the malignancy.

Therapy may be held or reduced due to the risk of TLS, until exchange transfusion is able to reduce the total WBC in order to prevent TLS.

c. Determine the type of exchange transfusion needed based on patient's weight and institutional resources

Double volume exchange using pheresis

Manual double volume exchange transfusion

Activate the blood bank as soon as possible, as an exchange transfusion requires 160 cc/kg of blood which has been reconstituted to the appropriate hematocrit using either normal saline or albumin

Establish good peripheral or central venous access depending on the requirements of the local pheresis service or clinical need

MM

Rapid assessment of the airway. If there are associated signs and symptoms of airway compromise prepare for emergent therapy of the tumor in consultation with hematology oncology and possible radiation oncology

The majority of anterior mediastinal masses that cause airway compression are lymphoid malignancies (T-cell leukemia or lymphoma, Hodgkin's disease) which will respond rapidly to steroids. Prednisone is generally dosed at 60 mg/m2/day in divided doses.

Consider airway support that can assist the conscious patient such as continuous positive airway pressure (CPAP or BiPAP, not intubation which requires sedation) or heliox

Assessment of hyperleukocytosis and TLS, especially if steroids are initiated

Avoid anxiety provoking procedures, and allow the patient to find their position of comfort

Rapid assessment of the neurologic status of a patient with upper extremity edema, emphasizing mental status and focal neurologic deficits

Assessment of TLS and MM as above

Appropriate imaging to determine if the cause of SVCS is due to intraluminal obstruction (ie thrombosis) or extraluminal compression

If SVCS is due to thrombosis, initiate heparin drip or LMWH per institutional guidelines. Be sure to evaluate for possible contraindications to heparin, such as intracranial bleed, if clinical suspicion exists.

If SVCS is due to extraluminal compression, consult hematology oncology and radiation oncology to initiate appropriate therapy. Therapy may need to be emergent without biopsy if patient is showing rapid neurologic deterioration.

FN

Rapid triage and assessment of the patient who presents with fever or signs and symptoms of shock with a recent history of chemotherapy

Immediately access the CVL to obtain cultures and appropriate blood work

Immediately administer an appropriate antipseudomonal IV antibiotic, even if the patient's blood work is not yet back

Extended history and physical to appropriately determine the patient's risk group as listed above and expand antibiotic coverage as described above

Admission and close monitoring for shock prior to and after the start of antibiotics

Hospital observation until discharge criteria have been met. In our institution this would be negative cultures for at least 48 hours, afebrile for at least 24 hours, and evidence of count recovery. If the stay is associated with any signs or symptoms of shock, or if an organism is cultured, longer courses of antibiotics may be appropriate, even after count recovery.

Typhlitis

Rapid assessment and treatment as outlined under FN

Appropriate assessment of the abdomen. If guarding or rebound is present appropriate imaging and surgical consultation should be obtained immediately

Initiate appropriate levels of pain control

Manage associated symptoms such as diarrhea or constipation

If prolonged course is expected, should assess nutritional needs and determine if TPN is appropriate

SCC

Suspected when the history or neurologic exam demonstrates a sensory level, or decreased strength and increased reflexes bilaterally below a specific spinal level. Rectal tone should be assessed, as well as any recent history of urinary or fecal incontinence. Physical should also assess for point tenderness over the spine.

Emergent imaging of the spine if SCC is suspected with either MRI or CT.

Consider spinal injury doses of steroids. Remember that steroids may make the diagnosis of a lymphoid malignancy impossible, and may precipitate or worsen TLS.

Emergent consultation with neurosurgery, hematology oncology, and radiation oncology to determine the best course of action to relieve the compression. In some cases chemotherapy may be as effective as neurosurgery.

Drugs and dosages

TLS

Hyperuricemia

Allopurinol

<10yo: 10 mg/kg/day divided 2-3x's a day, max 800 mg/day

>10 yo and adults: 600-800 mg/day divided 2-3x's a day

Rasburicase

0.2 mg/kg/dose IV once daily for up to 5 days

Contraindicated with G6PD deficiency

Treatment of electrolytes

Oral calcium supplements based on institutional preference

Calcium gluconate (IV) - not recommended unless concern of immediate harm to the patient due to complications of hypercalcemia

Amphogel

20-150 mg/kg/day divided every 4-6 hours

Treatment of hyperkalemia

Sodium bicarbonate (IV) based on institutional policy

Calcium gluconate (IV) based on institutional policy

Albuterol

0.3 mg/kg/hour via continuous nebulization

Insulin and glucose

Glucose 0.5-1 g/kg combined with

Regular insulin 1gm per 4 gram of dextrose infused over 2 hours. This should be a continuous infusion until hyperkalemia is resolved

Note this may need correction for renal impairment

Lasix

1-2 mg/kg IV every 6 hours

Note this is only used to encourage excretion of potassium, not to maintain urine output

Kayexolate

Hyperleukocytosis

ALL

Steroids at 40-60 mg/m2/day

AML

Low dose cytarabine

CML

Hydroxyurea

Low dose cytarabine

SVCS

Anticoagulation

Heparin drip

LMWH

FN

Appropriate antipseudomonal IV antibiotics

Ceftazadime

Piperacillin

Pipercillin and clavulanate

Ticarcillin

Ticarcillin and

Imipenem

Meropenem

Gram positive coverage

Vancomycin

Linezolid

Anaerobic Coverage

Clindamycin

Metronidazole

Imipenem

Meropenem

Aminoglycosides

Gentamycin

Tobramycin

Amikacin

Growth Factors

Granulocyte culture stimulating factor (GCSF)

Granulocyte Monocyte culture stimulating factor (GMCSF)

Typhlitis

Pain

Oral

Rapid release

Hydrocodone

Oxycodone

Sustained release

Oxycontin

Methadone

IV

Morphine

Dilaudid

Fentanyl

PCA delivery systems

SCC

Steroids

Chemotherapy

Radiation

Refractory cases

TLS

In the setting or refractory renal failure or hyperkalemia, despite all measure listed above, dialysis or CVVH remains the final treatment until renal function recovers. As long as the malignancy responds to chemotherapy, renal function is very likely to return to baseline, although the time frame for that is variable.

Hyperleukocytosis

Plasmapheresis should always be considered for WBC counts that exceed mentioned thresholds. Remember that WBC live in the interstitial space as well as the vascular space. Therefore, many patients will experience a rebound after the initial reduction 12 to 24 hours following the procedure. Therefore pheresis once a day for several days in a row may be needed.

Initial therapy should also be introduced, and treatment of TLS should be established quickly.

In the setting of ALL, very few initial presentations will be steroid refractory. Therefore treatment with steroids, after plasmapheresis, in addition to treatment of TLS, should be effective.

CML is very responsive to oral hydroxyurea and low dose cytarabine. These medications will gently reduce the total tumor burden while imatinib is started for definitive control, and TLS measures are being followed. If the patient doesn't respond to these three medications, blast crisis in CML (the transition of CML to AML) should be considered, as the AML occurring after CML is particularly refractory, and may require full dose AML chemotherapy for control.

Plasmapheresis may also be used in CML to control the WBC, although its benefits are not prospectively studied in the pediatric population in CML.

In the setting of relapsed ALL, or AML, however, low dose or partial dose therapy may not control the disease due to disease resistance. Therefore plasmapheresis with treatment of TLS is the standard for these entities, with initiation of full dose chemotherapy to induce remission.

For T-cell leukemia, only 50% of relapses make it back into remission despite reinduction therapy, and very few survive long term even with allogeneic transplant. Therefore, full dose chemotherapy is warranted if steroids alone fail to reduce the WBC count.

AML, new or relapsed, tends to be more resistant to treatment. Therefore full induction therapy is warranted in almost all situations.

MM

Emergent treatment with steroids, chemotherapy, and radiation for patients who are felt to have a high risk of losing their airway. If a patient loses his/her airway below the level of intubation, that patient will need to be placed on ECMO emergently as intubation cannot relieve the obstruction.

SVCS

a. External compression of the SVC is generally removed using chemotherapy or radiation, depending on the tumor type. If the event that these modalities are not effective, emergent debulking of the mass with surgery is an option. Consultation with pediatric surgery, or with the appropriate subspecialty surgeon should be considered.

b. Occlusive or near occlusive thrombosis of the SVC is generally handled with heparin, either by IV drip, or with subcutaneous LMWH. If a patient's neurologic status is deteriorating without CNS hemorrhage (venous infarction), then thrombolytics, either catheter directed or systemic can be considered although there is significant risk of bleeding with these medications. Generally hematology, interventional radiology, interventional cardiology or vascular surgery have the most experience with thrombolytics, although this is institution specific.

If there is evidence of CNS hemorrhage or infarction, thrombolytics are contraindicated, and heparin therapy is controversial. Surgical thrombectomy, either by general or vascular surgery, interventional radiology, or interventional cardiology should be considered.

FN

Refractory cases of FN become sepsis. Consideration can be given to the use of WBC growth factors such as GCSF and GMCSF, as well as granulocyte infusions. There is no clear data that any of these interventions improve the outcome of a neutropenic patient with sepsis.

Typhlitis

Rigorous treatment of pain with PCA is the standard of care. Treatment of associated sepsis as per FN guidelines initially and sepsis guidelines if the infection progresses. Complications of typhlitis include obstruction, perforation and gastrointestinal bleeding. If those side effects occur, consult pediatric surgery for management recommendations and possible surgery.

SCC

Treatment options as stated above include initial steroids, chemotherapy, radiation, and at our institution, surgery as a last resort. If steroids, chemotherapy and or radiation have failed, laminectomy or laminotomy should be considered. Note that the longer the patient has loss of function, the less likely to recover. Therefore, hematology oncology and neurosurgery should be on board as soon as this is discovered in order to make rapid decisions both initially and during reassessment.

Historically treatment has been laminectomy with removal of the tumor from the spinal canal. in the last ten years, there is a growing recognition that chemotherapy for many pediatric tumors may be efficacious as surgery. Given that the patient is going to have the chemotherapy regardless, many pediatric oncologists are pushing for chemotherapy upfront rather than surgery. Long term complications of laminectomy is primarily mild to severe scoliosis depending on the length of the laminectomy. If a patient can avoid this complication that would be preferable. This decision requires a multidisciplinary discussion.

5. Disease monitoring, follow-up and disposition

Monitoring and disposition

TLS

monitoring

Frequent monitoring of electrolytes, uric acid, and renal function up to every 4 hours for severe cases. As the first days of therapy pass, and tumor burden drops with therapy, these can be dropped in frequency

Periodic EKG for potassiums greater than 6 (Units)

Close monitoring of fluid balance and urine output

Follow-up and disposition

For patients who avoid dialysis, once the tumor burden has been reduced with chemotherapy, the patient can be transferred from the unit to the hematology oncology service. Mild renal injury, determined by increasing creatinine, generally recover fully.

For those patients who required dialysis and CVVH, full recovery is generally the rule. Hematology oncology and nephrology services will determine the ultimate disposition.

Hyperleukocytosis

Monitoring

Frequent monitoring for TLS as above

With plasmapheresis or manual exchange transfusion, calcium levels can drop due to the anticoagulants used during pheresis, or stored with the PRBC. Monitor calciums before and after exchange transfusions

Frequent neuro checks to watch for intracranial events

Follow-up and disposition

Once the WBC has been reduced, either with pheresis or chemotherapy, the patient can be transferred to the hematology service. Hyperleukocytosis establishes that the patient has a high risk leukemia. Overall survival can be anywhere from 30-70% depending on the leukemia classification.

For those patients successfully treated without airway compromise, clinical exam should predict when they are able to be transferred to the hematology oncology service. Simple chest X-rays will demonstrated the shrinkage of an anterior mediastinal mass originating in the thymus, and potentially hilar adenopathy. Imaging with CT scan may be necessary to determine if a posterior mediastinal mass is shrinking, but these are less likely to cause airway compromise.

Survival of patients with MM who did not obstruct is dependent on the underlying malignancy

For those patients who require procedures such as ECMO, please refer to the ECMO section for disposition

SVCS

Monitoring:

For extravascular compression

Monitoring of TLS as above

Monitoring of the neurologic status to ensure that the patient is not having focal neurologic events or changes in mental status.

2. For intravascular obstruction (blood clot)

Monitoring of TLS as above

Monitoring of the neurologic status to ensure that the patient is not having focal neurologic events or changes in mental status

Monitoring of heparin, whether heparin drip or LMWH, should be done per institutional standards. LMWH in generally checked with an activated factor X level (Factor Xa level), and heparin drips can be followed with PTTs or Factor Xa levels. Heparin drips require much more frequent monitoring (every four hour PTTs) until target anticoagulation is achieved. Then heparin drips are monitored every 24 hours generally.

In our institution, imaging of the clot within 72 hours of initiating anticoagulation is done to ensure that the clot is not enlarging. If enlarging, despite therapeutic levels of heparin, other treatments discussed above should be considered.

Assessment of inheritable causes of thrombosis (factor V leiden, prothrombin gene mutation, Proteins S deficiency, protein C deficiency, ATIII deficiency) should be considered on a case by case basis, after a thorough family history has been obtained.

Follow-up and disposition:

Once extravascular compression has been relieved, whether by chemotherapy, radiation, surgery or a combination, the patient may be transferred to the hematology oncology service for further therapy. Prognosis is dependent on the underlying malignancy.

Once intravascular compression is successfully anticoagulated, and the clot is documented as stable without propagation, the patient can be transferred to the hematology oncology service. Usually heparin drips are converted to either LMWH or oral warfarin for long term anticoagulation. In our institution, once a clot is demonstrated, anticoagulation is continued for a minimum of three months unless there is a medical contraindication. Prognosis is dependent on the underlying malignancy.

FN

Monitoring

Once the patient is triaged and the appropriate antibiotics have been selected, the patient should be monitored with frequent vital signs and exact measurements on input and output. Signs and symptoms of shock should be treated aggressively as per the sepsis guidelines, first with fluids and then with other medications such as dopamine and possibly hydrocortisone based on recent therapy.

Generally, signs of shock would present within 72 hours of the first dose of antibiotic if related to the original fever. However, secondary infections should be watched for, and other types of infections which are unresponsive to antibiotics (viral, fungal, etc) should be considered if the fever continued despite appropriate antibiotic selection.

For patients admitted on a single anti pseudomonal antibiotic (low risk) at our institution, we will continue to add antibiotics over the first five days after admission. If the fever continues past 48 hours after admission we will add vancomycin. If the fever continues beyond 72-96 hours we consider adding an aminoglycoside. And if the fever continues beyond 5 days after admission and appropriate antibiotics, we add empiric antifungal coverage,

The use of broad spectrum antibiotics can predispose the patient to fungal infections. In general, there are two types of fungal infections, candidal infections, and molds (ex: aspergillus). Our first line antifungal is liposomal amphotericin (Ambisome) as it has fewer side effects and has the broadest spectrum of coverage.

Disposition

We use three criteria for discharge after fever neutropenia: Resolution of fever for at least 24 hours. Cultures negative for at least 48 hours. Evidence of count recovery for two to three days in a row.

Transfer from the ICU only requires that the patient is stable without signs or symptoms of shock.

Typhlitis

Monitoring

Symptoms may improve with the initiation of antibiotics and pain control; however, severe cases of typhlitis may take weeks for the patient to fully recover (no abdominal pain, normal diet). Close monitoring of the abdominal exam is warranted to ensure that acute abdomen does not develop, This may be difficult to assess in the setting of narcotic use.

Weight must be watched in the setting of decreased oral intake. Use of enteral feeds through a nasogastric tube may be considered, but many times is difficult because of increased pain. In the setting of pneumatosis or obstruction, NG feeds are generally contraindicated. Early initiation of total parenteral nutrition should be considered if the patient is not eating adequately.

Generally, symptoms should begin to improve with count recovery.

Disposition

Discharge is very dependent on the patient. We generally would like the patient on oral pain medication. Generally we would like the patient to be taking a regular diet, although this is variable.

Transfer from the ICU can occur when the patient is stable on therapy, without signs of an acute abdomen or sepsis

SCC

Monitoring

Monitoring mainly consists of frequent neurological assessments.

For patients with intravascular thrombosis, initial monitoring of the heparin drip should occur relatively frequently per institutional guidelines, until therapeutic levels of heparin are achieved and stable. For patients on LMWH, monitoring is generally done every twenty four hours (every two doses) until therapeutic levels are established.

Disposition

Discharge for the ICU only requires that the patient's neurologic status is stable and not getting worse. In addition, many hospitals have internal standards as to where a heparin drip can be managed within the hospital.

Discharge from the hospital is determined by the treatment of the underlying malignancy.

Incorrect diagnosis

TLS

if markers of TLS are not abnormal (uric acid, calcium, phosphorus), but renal failure is evident in the setting of malignancy, then other causes of renal failure should be considered, such as obstructive renal failure.

If there is evidence of TLS in the setting of renal insufficiency or failure, but no malignancy can be found, consider other conditions with massive rapid cell death such as rhabdomyolysis.

Hyperleukocytosis

Nucleated red cells (states of high marrow output such as inborn or autoimmune hemolytic anemia) can be misread on a CBC as WBC, falsely elevating the WBC count. Review of the smear will demonstrate nucleated RBC and possibly abnormal red cell forms depending on the cause of the hemolytic anemia.

Leukemoid reactions (elevated WBC due to an inflammatory but non-malignant condition such as sepsis) can elevate the white count acutely. On smear, the white cells will show reactive and immature forms, but at all levels of development. Many times granulocyte cell lines predominate (segs, bands, and their precursors). Treatment for the underlying condition will generally improve the white count within several days. Other markers of TLS should be negative as long as renal function is adequate.

Transient myeloproliferative disorder may occur in young patients with trisomy 21. This condition is associated with an elevated WBC with blast forms in the marrow and peripheral blood, and looks like new onset AML. The history of trisomy 21 is important, however, and point to TMD vs frank AML.In general, the white count generally does not go above 100,000 (units), but can. Physical exam can show splenomegaly and other signs consistent with AML. Infrequently these patients are treated with low dose cytarabine or hydroxyurea if the WBC is felt to be too high (generally over 100,000). This condition spontaneously resolves within weeks to months, but these patients then have a 25% risk of developing AML later in life.

MM

Usually there is not an argument that there is some type of lesion on CXR causing a mass effect. The concern is usually whether that lesion is malignant, structural, or infectious. Regardless, airway precautions should always be followed if there is a question of tracheal compression while other diagnostic imaging and surgery is pursued.

SVCS

For extravascular compression please see MM above.

For intravascular thrombosis, the level of thrombosis needs to be fully evaluated. Cardiac involvement, or jugular extension may require further consultation with other services such as cardiology, thoracic surgery, or vascular surgery.

Please note that if SVCS is suspected and there is an acute change of mental status, evaluation for other causes of acute mental status change should be considered in addition to SVCS.

FN

Artifactual neutropenia can be caused by margination of PMNs. This can occur with acute stress such as infection or with steroid administration. In reality these patients have adequate numbers of granulocytes, and respond appropriately to infection.

Autoimmune causes of neutropenia should be considered in the patient with a long history of illness, not otherwise diagnosed. These patients can have variable responses to infection; they may be completely appropriate, or may act as a fully neutropenic patient. We recommend treating all patients with neutropenia and fever as immunodeficient until proven otherwise.

All oncology patients with recent history of chemotherapy should be assumed neutropenic and treated appropriately prior to CBC results being obtained

Typhlitis

Common causes of acute abdomen should always be considered and potentially ruled out when considering the diagnosis of typhlitis. These include but are not limited to acute appendicitis, peritonitis, cholelithiasis, pyelonephritis, and in the sexually active teenager, PID and pregnancy.

SCC

As with many other oncologic emergencies, the question is not whether the condition exists, but whether it is a malignant process causing the spinal cord compression. Spinal cord compression can be caused by many different processes such as bleed, trauma, fluid collection, abscess, and benign neoplasms. These different etiologies should be answered by MRI of the spine.

Transverse myelitis can present very similarly to malignancy, but is an intrinsic process to the cord itself.

Follow-up

TLS

Generally the process resolves within two to seven days of the start of therapy

If renal function returns to baseline no specific follow-up is needed

Follow-up per oncology and nephrology

Hyperleukocytosis

Generally the process resolves with initiation of chemotherapy within two to seven days

Follow-up per oncology

MM

No specific follow-up is needed for this condition.

Follow-up per oncology

SVCS

For extravascular compression, follow-up is per surgery, radiation oncology, and oncology depending on the treatment used. No specific long term follow-up is needed beyond treatment.

For intravascular thrombosis, anticoagulation should remain in place for 3 months at therapeutic doses if there are contraindications. This will require monitoring per the type of anticoagulation used.

FN

Once the neutropenia resolves, there is no need for further follow-up beyond normal oncology follow-up

Typhlitis

Depending on the severity of the condition specific treatments may require specific follow-up such as weaning pain medications and outpatient TPN. Beyond these treatments, no further specific follow-up is needed beyond normal oncology follow-up.

SCC

Follow-up is dependent on the status of the patient. If dysfunction remains after initial treatment, referral to physical therapy and rehabilitation centers may be warranted. Long term follow-up with neurology should be considered to follow status. Otherwise, oncology follow-up should be adequate

Pathophysiology

TLS

TLS is the result of rapid cell lysis. Malignancy, especially hematologic malignancy, is characterized by increased cell proliferation, and increased cell death. TLS results when the byproducts of this rapid cell death exceed the capacity of the renal clearance. Specifically, these by-products are uric acid, the result of purine degradation, phosphorous and potassium.

a. Purine metabolism and uric acid

To review, purines are degraded to xanthine and hypoxanthine, which is then converted to uric acid by xanthine oxidase. Degradation in primates stops at that point. Urine acid is relatively insoluble which is the primary problem in TLS.

The pKa of uric acid is 5.75, which means that below a urine pH of 5.75 uric acid is in its neutral form, which limits its solubility in urine. A pH above 5.5 causes uric acid to release a hydrogen molecule, converting the molecule to urate, facilitating its solubility. At a pH of 7, approximately 98% is in its urate state. This is why bicarbonate has historically been used to alkalinize the urine.

Uric acid is primarily secreted into the nephron. Uric acid is freely filtered by the glomerulus, but is what is secreted is almost complete reabsorbed in the proximal tubule. Seventy percent of uric acid is removed by the kidney, 30% by the hepatobiliary route.

Hydration is very important in controlling uric acid excretion. If more urine can be created this allows more uric acid to be dissolved, and therefore excreted in the urine.

Allopurinol inhibits xanthine oxidate, preventing the creation of uric acid. Hypoxanthine is much more soluble than uric acid facilitating excretion. Xanthine is less soluble that uric acid, and may still contribute to renal failure in severe cases.

Rasburicase is an enzyme that is present in all mammals. In primates, there has been a missense mutation in the promoter of the gene which prevents its transcription. The enzyme continues the metabolism of uric acid further into allantoin, which is very soluble.

b. Phosphorous and calcium

Phosphorous generally maintains a zero balance on a daily basis; gut absorption is equaled by renal excretion. Generally a well functioning kidney can excrete heavy phosphorous loads. However, when there is a phosphorous challenge as in TLS, especially in association with renal insufficiency and/or dehydration, the kidney may be unable to excrete the phosphorous load, mostly due to decreased renal perfusion (prerenal and renal).

If the product of the calcium concentration and phosphorous concentration reaches 60, calcium phosphate crystals begin to precipitate. This can especially occur in the kidney where alkaline pH and elevated concentrations of the minerals may worsen renal failure. If the pH of the urine is >8.5, this will increase precipitation, which is why alkalinization of the urine is somewhat controversial.

c. Calcium

Hypocalcemia primarily results from elevated phosphorous levels and precipitation. Calcium is used as a signaling molecule in skeletal muscle, cardiac muscle, and the central nervous system (among others). Low levels of calcium result first in skeletal muscle spasm (at serum levels of 6-7 (units)). Levels between 5-6 can be associated with decreased cardiac function and arrhythmia, and would be considered an emergent reason for treatment with IV calcium. Levels less than 5 (units) are associated with seizures that will abate only with increased levels of calcium.

d. Potassium

Hyperleukocytosis

The pathophysiology of hyperleukocytosis is related to the underlying malignancy.

With ALL, the malignant cells are very susceptible to treatment with chemotherapy and steroids. Therefore, even small amounts of treatment can cause a large drop in the total WBC. For that reason, TLS is the main side effect of ALL related hyperleukocytosis.

With AML, the malignant cells are more resistant to treatment. Therefore, TLS less of a problem in AML with bulky disease or hyperleukocytosis. Instead, total blood viscosity becomes more significant and risk of vaso-occlusion, especially in the lung and the CNS increases.

Specifically in AML M3 (acute promyelocytic leukemia or APML) the leukemic blasts express fibrinolytic enzymes on the cell surface. These patients frequently present with bleeding and clinical DIC. The bleeding can be life threatening if in the lungs or intestines. CNS bleeds and infarction are both reported.

MM

Large masses in the chest can exert pressure of the trachea or the mainstem bronchi, increasing airway resistance, and compromising gas exchange.

Masses that occur in the neck outside of the rib cage generally present with stridor, usually inspiratory. As the diaphragm generates negative pressure, the upper trachea experiences a collapsing force during inspiration which is responsible for stridor. Within the chest, the expansion of the chest wall counters the negative force of inspiration, and pulls the airway open, so there are usually no inspiratory sounds. However on expiration the chest wall exerts pressure on the airway, causing a choke point where the positive pressure of the airway (expiration by the diaphragm) equals the pressure being exerted by the chest wall.

This is exacerbated by the external compression of the mass, so that wheezing may be heard. Wheezing from a large airway is different from small airway wheezing (as in RAD). The wheezing may sound like a whistling, and be more of a solitary sound, located in one section of the chest.

The trachea of the neck has thick cartilage rings that prevent compression in all but the most extreme cases.

The body compensates primarily for intrathoracic mass by increasing use of accessory muscles, applying more force to bypass the obstruction. In the case of anterior mediastinal masses, the patient may also assume a tripod position, or position of comfort, which leans the mass forward and off the trachea. Sedating the patient removes both of these compensatory mechanisms.

Lastly, there have been deaths from MM attributed to pulmonary artery compression. There is no way to assess compromise of pulmonary artery flow at this time.

SVCS

SVCS implies that the SVC is either partial or completely obstructed, either due to internal obstruction (thrombosis) or external compression.

The hallmark of venous obstruction is swelling and congestion distal to the occlusion, and this would involve one or both upper extremities and the head and neck. There is not a good system of collaterals available for the upper circulation. Therefore venous pressure may rise to systemic pressures in the setting of complete obstruction.

In this scenario, as venous pressures rise to match systemic pressures, the patient may experience venous infarcts. Arterial perfusion is impaired as venous pressures rise, and the pressure gradient across the capillary approaches zero. On pathology or imaging, enlarged venules can be noted, which is the hallmark of this condition.

Factors leading to thrombosis relate to Virchow's triad: hypercoagulability (from the cancer itself, CVL placement, etc), stasis (compression by the tumor, or obstruction due to clot), and endothelial injury (thrombosis). Pediatric malignancy can cause SVCS due to one or all of these categories. It is important to distinguish the cause as treatment can change with the cause. For example, a clot may be treated with line removal, and heparin or TPA; compression may need to be treated with stent placement or surgical decompression if possible.

FN

Translocation of bacteria from our skin, GI tract, or respiratory tree occurs every day in most individuals. However, only a small percentage of these occurrences are associated with illness. This is due to an immediate response of the innate immune system. Neutrophils comprise the major cellular response to acute bacteremia, and when they are absent, these common bacteremias can lead to life threatening infection.

Neutrophils divide and mature in the bone marrow over a 21-day period, which incidentally is why traditionally chemotherapy is given in 3-week cycles to allow recovery.

The growth period begins with rapid expansion lasting for about 11-14 days. During this period, the neutrophils are maturing, but also have the ability to expand and divide. The last 7-10 days in the marrow, these cells continue to mature, but lose their ability to divide. This 7-10 day maturation window explains why patients do not become neutropenic immediately upon receiving chemotherapy: since these cells are only maturing and not dividing, they are not sensitive to the affects of chemotherapy, which attacks rapidly dividing cells.

Once these maturing cells in the bone marrow are depleted, the patient becomes neutropenic, usually 7-10 days after chemotherapy.

Once the chemotherapy is completed the bone marrow immediately begins regenerating, creating new neutrophils (and all of the other cell lines). But there is a 21-day window till those cells are mature enough to be found in the peripheral circulation. This usually leaves a 10-14 day window of neutropenia.

During that time period the patient is at increased risk of spontaneous bacterial infection. If other aspects of the immune system are compromised (mucosal breakdown for example) that risk will be increased.

Typhlitis

Typhlitis occurs when bacterial are able to translocate from the lumen of the gut to the wall of the intestine. In the early 80s when this condition was defined, it was identified with RLQ pain similar to that identified with appendicitis. Therefore the original definitions of typhlitis located the bacterial infection of the gut primarily to the cecum. Today this condition is recognized to occur throughout the length of the intestine. This has been referred to bacterial overgrowth within the intestine.

There can be a component of bacterial overgrowth with pathogenic bacteria that are normally restricted in their growth by neutrophils, but even routine bacteria become dangerous in this situation.

Infection of the intestinal wall leads to edema and inflammation. Radiographically the intestine can show ileus and pneumatosis. Invasion of the intestinal wall can have an increased risk of bacteremia. Swelling and edema can lead to GI bleed and perforation in the most severe cases.

SCC

There are many mechanisms of SCC, and many of them can be caused by oncological conditions. Compression from a bony metastasis to the spine, chloroma formation, or direct invasion of the spinal space from a paraspinal mass with extension through the neural foramen is one mechanism. This can be complicated by local edema and swelling of the spinal cord itself.

Treatment such as radiation can cause injury to the cord causing swelling as described above.

Infections, such as meningitis or epidural abscesses can cause compression to the cord.

Fracture of vertebral bodies due to bony metastases or ALL can rarely lead to cord compression.

Historically treatment has been laminectomy with removal of the tumor from the spinal canal. in the last ten years, there is a growing recognition that chemotherapy for many pediatric tumors may be as efficacious as surgery.

Given that the patient is going to have the chemotherapy regardless, many pediatric oncologists are pushing for chemotherapy upfront rather than surgery. Long term complications of laminectomy is primarily mild to severe scoliosis depending on the length of the laminectomy. If a patient can avoid this complication that would be preferable.

Epidemiology

NA

Prognosis

TLS

The outcome of mild to moderate TLS which is handled with hydration, treatment for uric acid, and treatment of the malignancy rarely if ever has long term complications. Even TLS severe enough to require dialysis generally reverses without long term complications.

Hyperleukocytosis

The prognosis of hyperleukocytosis relates to the underlying disease and the complications that occur during the presentation (TLS, stroke, ARDS). Generally outcome of patients with hyperleukocytosis is excellent, as long as the aforementioned complications have not occurred.

MM

The prognosis of MM relates to the underlying disease and the complications that occur during the presentation (respiratory failure). Generally outcome of patients with MM is excellent, as long as the aforementioned complications have not occurred.

SVCS

The prognosis of SVCS relates to the underlying disease and the complications that occur during the presentation (venous thrombosis, venous infarcts). Generally outcome of patients with SVCS is excellent, as long as the aforementioned complications have not occurred.

FN

The prognosis of FN relates to the underlying disease and the complications that occur during the presentation (sepsis). Generally outcome of patients with FN is excellent, as long as the aforementioned complications have not occurred.

Typhlitis

The prognosis of typhlitis relates to the underlying disease and the complications that occur during the presentation (ileus, pain, infection, perforation, GI bleed). Generally outcome of patients with typhlitis is excellent, as long as the aforementioned complications have not occurred.

SCC

Outcome of SCC depends on many variables, including tumor compression, duration of symptoms and underlying tumor.

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